Genetic Variant FLI1:c.-646_-635delGAGAGAGAGAGA (chr11-128693941-CGAGAGAGAGAGA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000281428.12(FLI1):c.-646_-635delGAGAGAGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 175,638 control chromosomes in the GnomAD database, including 39 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.022 ( 37 hom., cov: 0)

Exomes 𝑓: 0.034 ( 2 hom. )

Consequence

FLI1
ENST00000281428.12 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Publications

0 publications found

Variant links:

Genes affected

FLI1 (HGNC:3749): (Fli-1 proto-oncogene, ETS transcription factor) This gene encodes a transcription factor containing an ETS DNA-binding domain. The gene can undergo a t(11;22)(q24;q12) translocation with the Ewing sarcoma gene on chromosome 22, which results in a fusion gene that is present in the majority of Ewing sarcoma cases. An acute lymphoblastic leukemia-associated t(4;11)(q21;q23) translocation involving this gene has also been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

FLI1 links:

SENCR (HGNC:44177): (smooth muscle and endothelial cell enriched migration/differentiation-associated lncRNA)

SENCR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLI1	NM_002017.5 link	c.-317_-306delGAGAGAGAGAGA		upstream_gene_variant		ENST00000527786.7	NP_002008.2	Q01543-1A0A024R3M5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLI1	ENST00000527786.7 link	c.-317_-306delGAGAGAGAGAGA		upstream_gene_variant		1	NM_002017.5	ENSP00000433488.2		Q01543-1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

1780

AN:

82798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0595

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.0210

Gnomad SAS

AF:

0.00797

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.0214

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.0181

GnomAD4 exome

AF:

0.0336

AC:

3115

AN:

92816

Hom.:

AF XY:

0.0328

AC XY:

1445

AN XY:

44082

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0359

AC:

140

AN:

3896

American (AMR)

AF:

0.0691

AC:

186

AN:

2690

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

AN:

5328

East Asian (EAS)

AF:

0.0459

AC:

523

AN:

11402

South Asian (SAS)

AF:

0.0142

AC:

AN:

1764

European-Finnish (FIN)

AF:

0.0464

AC:

AN:

1982

Middle Eastern (MID)

AF:

0.0194

AC:

AN:

566

European-Non Finnish (NFE)

AF:

0.0320

AC:

1851

AN:

57852

Other (OTH)

AF:

0.0307

AC:

225

AN:

7336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.322

Heterozygous variant carriers

202

404

605

807

1009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0215

AC:

1783

AN:

82822

Hom.:

Cov.:

AF XY:

0.0225

AC XY:

861

AN XY:

38182

show subpopulations

African (AFR)

AF:

0.0163

AC:

301

AN:

18428

American (AMR)

AF:

0.0601

AC:

470

AN:

7822

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

2484

East Asian (EAS)

AF:

0.0211

AC:

AN:

2702

South Asian (SAS)

AF:

0.00756

AC:

AN:

2116

European-Finnish (FIN)

AF:

0.0148

AC:

AN:

3184

Middle Eastern (MID)

AF:

0.0224

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0194

AC:

858

AN:

44212

Other (OTH)

AF:

0.0179

AC:

AN:

1174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-128693941-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA-CGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over